Glaucoma beyond the eye: Recent achievements
on the systemic dysfunction of this disease.
Nuno Pinto Ferreira1,2; Luís Abegão Pinto1,2; Carlos Marques-Neves1,2
1Serviço Oftalmologia, Hospital de Santa Maria - Centro Académico de Medicina de Lisboa 2Universidade de Lisboa, Faculdade de Medicina, Centro de Estudos Ciências da Visão
IntroductIon
Glaucoma is a chronic irreversible optic neuropathy cha-racterized by a slowly progressive loss of retinal ganglion cells. Clinically, it is defined by optic nerve head cupping and visual field defects, both of which are related to optic nerve head (ONH) remodelling. A major risk factor for the development of glaucoma is an elevated intraocular pressure. This discovery led to a clinical and surgical breakthrough for the management of our glaucoma patients where a low target IOP remains our main goal. Nevertheless, a number of studies came through and evolved our basic concept of glaucoma, showing that an increased IOP does not necessa-rily lead to glaucomatous optic neuropathy. Risk factors as a thin cornea and disk haemorrhages may be involved as well as other systemic factors. A number of studies suggest that primary open angle glaucoma may be a localized, ophthal-mological manifestation of a wider, systemic dysfunction. One particular segment of patients in which this may be important are the Normotensional glaucoma (NTG) patients, where disease progression has been linked to a vascular and autonomous nerve system (ANS) dysfunction. Some studies believe that this understanding might have therapeutic conse-quences in the future. This paper aims to review the relevant systemic findings in POAG published so far.
Glaucoma as a systemIc dIsease I - cardIoVascular system
Pache et al did a major review in 2006 on systemic findings associated with POAG.1 As described by them, the literature reveals some conflicting information about POAG and associated cardiovascular disease.
a. arteriosclerosis
No strong relationship exists between arteriosclero-sis or smoking and glaucoma.
B. Blood pressure
Most studies show an altered systemic blood pressure in glaucoma. However, the existing data are contradictory mainly because some of the studies are biased by their retrospective nature, a small sample, and methodology mis-conceptions, as no subgroups analysis of NTG and hyper-tension glaucoma (HTG) patients were performed.
1. Arterial hypertension
Studies reveal that POAG patients with elevated IOP are predisposed to systemic hypertension. However, blood pressure results are contradictory in NTG patients and controls, with some studies revealing a normal to high/low blood pressure (see below).
2. Arterial hypotension
Several studies show an association between POAG progression and low blood pressure for an accelerated optic nerve cupping and development of visual field defects, particularly in NTG. Markedly reduced systolic blood pressure during day and night is associated with progression despite well-controlled POAG and NTG. A study by Graham et al showed that HTG and NTG patients did not differ according to blood pressure, but all that showed progression had nocturnal lower blood pressure parameters.2 Tokunaga and co-workers later confirmed this finding suggesting that disturbance in the physiologic dip in nocturnal blood pressure may be involved in the progression of POAG patients.3 Ghergel et al evaluated the relationship between circadian blood pressure rhythm and retrobulbar blood flow in glaucoma patients. They found that an altered retrobulbar blood flow was present in patients with low nocturnal systemic blood pressure.4,5 Postural hypotension was also descri-bed as a risk factor for the progression of NTG.1 Kiuchi et al found an association between progression of visual field damage in NTG with IOP in the supine position and the magnitude of IOP elevation accompanying postural
changes. They suggested that deterioration in NTG may occur when patients are lying flat during sleep.6
Recently, Charlson et al in a prospective study found that the duration and magnitude of nocturnal hypoten-sion identify the patients with NTG which are more prone for visual field progression.7 As this finding was statistically significant, they recommended a routine ambulatory evaluation of blood pressure in all NTG patients, especially those who continue to progress des-pite IOP lowering treatment. They also concluded that blood pressure should be considered as a modifiable risk factor in NTG. Future randomized clinical trials are nee-ded to assess the efficacy of blood pressure management in NTG progression.
c. Vasospasm
Vasospasm is defined as inappropriate constriction or insufficient dilatation in the microcirculation to sti-muli, and has been proposed as an additional risk fac-tor in glaucoma. Gasser et al found that NTG patients showed a significant reduction of blood-flow velocity by nailfold capillaroscopy compared to controls, parti-cularly after cold provocation.8 The vascular dysregula-tion interferes with the autoreguladysregula-tion and renders the eye more sensitive to IOP increase and blood pressure decrease. This may be a feature in NTG as well as in HTG. In fact, in glaucoma patients have been found increased plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor. Emre et al found that ET-1 levels were significantly higher in the POAG patients with visual field progression.9 Another study found abnormal neuro--endothelial mechanisms of vascular tone control in NTG patients, related to the effects of ET-1 and neuropeptide Y, suggesting these findings as secondary to endothelial dysfunction and to autonomic nervous system dysregu-lation.10 However, Kunimatsu and co-workers, found no difference in plasma ET-1 level among NTG patients, HTG patients, and normal controls.11 More recently, Chen et al found no correlation between plasma levels of ET-1 and severity of glaucoma.12 The effects of ET-1 antagonists on glaucoma still need to be evaluated by clinical studies.
1. Electrocardiographic changes
The existing studies do not have an adequate study design to definitively answer whether ECG changes are an independent risk factor for glaucoma or not. There-fore, routine ECG screening in all glaucoma patients is not recommendable until larger, prospective, confirma-tory studies are available.
2. Headache and migraine
The majority of studies available on this topic sup-port an association between POAG (in particular NTG), and migraine. This might be based on the fact that both migraine and glaucoma are associated with systemic vas-cular dysregulation. Cursiefen and co-workers suggested an association between NTG and migraine and a potential, common vascular aetiology of both diseases.13 Pache et al concluded that was reasonable to ask glaucoma patients, and especially those with NTG, for symptoms of headache/ migraine when taking their medical history.1
d.Hemorheology
1. Platelet aggregation
There is evidence that POAG is associated with an alte-red platelet aggregation. The pathogenic role of an altealte-red platelet aggregation is not yet clear. Theoretically, is assu-med that the increased platelet aggregation might have a negative influence on the blood flow in the small branches of the short ciliary arteries supplying the optic disc. Medical interventions studies are needed to confirm this hypothesis.
2. Blood Viscosity
Despite different techniques, assessment of different parameters and small sample size, there is some evi-dence for an altered hemorheology in POAG. Blood or plasma viscosity are elevated and erythrocyte function and deformability seem to be decreased. For the other factors influencing hemorheology, such as fibrinogen, there are not enough data to draw firm conclusions.
3. Disc Haemorrhages
Recently, Patel et al tried to determine if glaucoma patients with a current optic disc haemorrhage (ODH), a known risk factor for glaucoma progression, had an increa-sed prevalence of nailfold haemorrhages compared with glaucoma patients without history of optic disc haemor-rhage. Nailfold capillaroscopy was performed and they concluded that there was no increase in nailfold haemor-rhages between the two groups. However, the prevalence of nailfold haemorrhages in patients with glaucoma either with or without an ODH is significantly greater than that identified in normal control subjects in other studies.14 Park and co-workers found that nail bed haemorrhage and loss of nail capillaries were strongly associated with the presence of optic disc haemorrhage, and the association was stronger with nail bed haemorrhage. No differences were observed between patients with NTG and patients with POAG.15 We find that recommending a nail cappillaroscopy in glaucoma patients is still in debate.
II - autonomous nerVous system
The influence of the autonomic nervous system on aqueous dynamics and, therefore, on IOP is well establi-shed; however, its precise mechanism is still not com-pletely understood.
Some studies, especially those conducted in patients with NTG, reveal that alterations in autonomic nervous system on glaucoma are not necessarily linked to an increased IOP. More likely, these findings support the idea that glaucoma might be a manifestation of more generalized autonomic nervous system dysfunction.1 Some of the changes seen are, a diminished oculo-car-dial reflex, abnormal cardiovascular reflex responses, reduction of the vagal control of the heart, significant reduction in diurnal and nocturnal heart rate variability, a reduced baroreceptor control and vascular dysregula-tion suggesting a decreased parasympathetic and sympa-thetic activity as well as sympasympa-thetic failure.
Riccadonna and co-workers found a significant reduction in diurnal heart rate variability in NTG com-pared with the HTG and control groups. They also found that nocturnal diastolic blood pressure variability was also reduced in NTG compared with controls, sugges-ting blunted blood pressure and heart rate modulation in NTG subjects.16
POAG treatment with autonomic agents must there-fore be studied prospectively in patients with autonomic systemic disturbances.
III - Immune system
Growing evidence suggests an association between POAG and changes in the immune system. Particularly in those with NTG, an autoimmune mechanism may be res-ponsible for the ONH damage either directly or by way of a mimicked autoimmune response to a sensitizing antigen.
a. autoimmunity
Some studies confirmed the presence of elevated serum levels of antinuclear antibodies (ANAs) and immunoglobulin G. NTG has been associated with a higher prevalence of autoimmune diseases relative to ocular hypertension (OHT) controls. Most studies rela-tive to the immunologic findings in glaucoma are only case reports or small case-control, cross-sectional stu-dies about a specific auto-antibody, their conclusions and relevance are therefore limited to our day practice.1
1. Monoclonal Gammopathy
Benign paraproteinemia although not necessarily asso-ciated with a systemic disease, it is considered to be a likely causative agent of peripheral neuropathies of various
origins. A study revealed that some NTG patients but none HTG presented paraproteinemia.17
2. Anti-rhodopsin antibodies
A study by Romano et al found an elevated anti--rhodopsin antibody count in NTG compared to HTG.18 These autoantibodies were analysed and found to be direc-ted toward the C-terminus of the rhodopsin molecule. Rhodopsin’s C-terminus shares sequence identity to some bacterial and viral proteins, what led the authors to specu-late about the possible presence of molecular mimicry.
3. Autoantibodies to Heat Shock Proteins (HSP)
HSP play an important role in cell survival both under normal and stress conditions (stress, anoxia, heat, ische-mic insults). In general, they have a protective role. They are highly immunogenic. Recent studies demonstrated the presence of serum autoantibodies to HSPs such as HSP27, aB- crystalline, and HSP60 in glaucoma patients. As long as no larger studies on this topic are available, no conclu-sions should be drawn.1
4. Autoantibodies to ONH glycosaminoglicans
Glycosaminoglycans have organizational and space--filling functions in tissue construction. They are also important for the maintenance of various cell functions and cell-to-cell interactions. Tezel et al demonstrated not only the presence of serum autoantibodies against ONH glycosa-minoglycans in glaucoma patients, (especially in those with NTG), but also immunostaining of glycosaminoglycans in the lamina cribrosa of postmortem glaucomatous eyes.19 A physiopathology relationship may be suggested by these findings
5. Neuron-specific Enolase (NSE) Autoantibodies
To date, the mechanism by which anti-NSE antibodies exert their apoptotic effect on retinal ganglion cells is not disclosed. Some studies revealed that anti-NSE antibodies were found significantly more often in glaucoma patients and were significantly higher in the early stages of POAG with visual field deterioration than without it. It has been suggested that the serum NSE autoantibodies might be a risk factor for retinal ganglion cell death in glaucoma.
6. Glutathione S-transferase
Glutathione S-transferases (GST) represent a major group of detoxification enzymes. Yang et al demonstrated increased titters of serum autoantibodies to GST relative to controls.20 They suggested that up regulation of GST in the glial cells might be a result from the glaucomatous damage,
and in some patients a secondary production of autoantibo-dies. Whether the circulating antibodies against GST have a pathogenic significance remains to be evaluated.
7. Antiphospholipid Antibodies
Studies are contradictory. According to Pache and Flammer unless larger prospective studies are available, the association between glaucoma and antiphospholipid antibodies remains to be established.1
8. Leukocyte activation, and their gene and protein expression in POAG
Some studies suggested that there is leukocyte migration inhibition in patients with POAG. Other studies revealed an increased subpopulation of CD8 and CD3 lymphocytes in the peripheral blood of NTG and HTG patients, suggesting that an autoantigen might be present in some patients with POAG to the retina and/or ONH.
Gene and protein expression in leukocytes was found to be altered in some studies with NTG patients. These revea-led that proteins involved in apoptosis as p53 and other regu-latory proteins as neural thread protein (NTP), 20S protea-some subunit XAPC7, matrix metalloproteinase 9 (MMP9) were overexpressed. The overexpression found in glaucoma patients may therefore be a consequence of repeated mild ischemia/reperfusion injury. The gene expression profi-les observed in these studies indicate the involvement of metabolic pathways characteristic for ischemia/reperfusion injury.1
The studies about leukocyte activation and glaucoma are limited by their small sample size and refer mainly to NTG. Larger confirmatory studies are desirable, and possible differences between NTG and HTG should be explored.
IV. endocrInoloGIcal system
a. diabetes mellitus
There is some controversy about the association of diabetes mellitus and POAG and ocular hypertension. Ellis and co-workers failed to confirm this association stating that at this moment we can not affirm that dia-betes is a risk factor for the development of POAG.21,22
B. thyroid disease
Pache and Flammer suggested that unless larger epi-demiological studies are available, a systematic screening for thyroid dysfunction in POAG patients seems unjusti-fied, but may be indicated in selected patients, as the rela-tionship between glaucoma and thyroid dysfunction is still in debate.1
1. Thyroid-associated orbitopathy (Graves Disease)
Thyroid-associated orbitopathy associated glaucoma can occur by several mechanisms, including elevated episcleral venous pressure, impaired outflow facility, and fibrosis of the extraocular muscles compressing the globe. Cockerham et al found that a subgroup of patients with thyroid-associated orbitopathy, might have an elevated IOP and that the duration of active orbital involvement is sta-tistically associated with the progression of glaucomatous damage.23 Ohtsuka and coworkers found a significantly higher prevalence of POAG and OHT among the patients with Graves disease when compared to the general popula-tion in Japan.24 However a recent review by Haefliger and co-workers found that in thyroid eye disease, glaucoma pre-valence does not seem significantly increased, and from a a pathophysiological standpoint the long term IOP increase is essentially due to episcleral venous pressure elevation and it should be differentiated with POAG.25,26
Therefore suggesting an association between thyroid eye disease and POAG seems unreasonable.
2. Hypothyroidism
The association between POAG and hypothyroidism is still controversial. No conclusions can be drawn to suggest a routine screening of hypothyroidism in glaucoma patients.
c. Pituitary system (acromegaly)
There are few studies describing the association of elevated levels of growth hormone and POAG. Howard and English reviewed 74 cases of acromegaly, and found among them an incidence of POAG of 10%.27 According to Pache and Flammer the observation of POAG in patients with acromegaly might suggest that the somatotropic hor-mone may promote a condition of glaucoma.
d. cushing syndrome
Cushing syndrome occurs when there is increased levels of glucocorticoids from and endogenous or exogenous source. The outflow of aqueous humour is decreased up to 50% in these patients. Recent studies refer that this effect is partially mediated by trabecular meshwork inducible gluco-corticoid response (TIGR) gene expression.1
Case studies report an association of Cushing syndrome and POAG. Rozsival and co-workers found the highest plasma and aqueous humour cortisol levels in patients with POAG who suffers also from systemic hypertension.28 McCarty and Schwartz found that both ocular hypertension (OHT) and POAG are associated with elevated levels of plasma free cortisol which were related to a reduced corti-sol binding capacity to albumin.29
Schwarts and co-workers later found that compared with normals, the OHT plus POAG subjects showed lower plasma cortisol levels in response to intramuscular ACTH, suggesting adrenal suppression in the OHT plus POAG group.30 Future research into the influence of glucocorti-coids on aqueous outflow may elucidate a possible associa-tion between these two disorders.
V. neurodeGeneratIVe dIseases
There is evidence that glaucomatous damage extends beyond the optic neuropathy also affecting the central ner-vous system (CNS): lateral geniculate nucleous and visual cortex. A direct consequence from the degenerative damage of the visual pathway.1
a. alzheimer disease
Alzheimer is a dementia characterized by the accumu-lation of large extracelular beta-amyloid plaques and intra-neuronal neurofibrillary tangles in the SNC.
Studies reveal a possible relationship between Alzhei-mer disease and glaucoma. Bayer and co-workers found a high occurrence rate of visual defects and/or optic disk cupping among patients with Alzheimer disease compati-ble with the diagnosis of glaucoma.31 It was also identified in the aqueous humour of glaucoma patients Alzheimer disease specific proteins, such as Alzheimer peptide (Ab) and alpha-1-antichymotrypsin. Apolipoprotein E (APOE) is involved in neuronal degeneration in Alzheimer disease. Inheritance of the APOE gene polymorphism, 34 allele, has been shown to be associated not only with an elevated risk for Alzheimer disease, but also for NTG in the Tasmanian population.32
Recently Tsilis et al did a major review about this topic suggesting that large and high-quality association stu-dies, preferably with long follow-up, are needed to clarify the existence and nature of possible associations between POAG and Alzheimer disease.33 Because an Alzheimer diagnosis can only be verified histologically, Pache and Flammer suggested the need of larger prospective post--mortem studies to assure an association between Alzheimer disease and glaucoma. A recent large cohort study by Kee-nan and co-workers found that the coexistence of these two disease is no different from that expected by chance. Howe-ver, the diagnosis of POAG was modestly associated with later development of vascular dementia, which the authors suggested as a consequence of shared vascular risk factors.34
B. Parkinson disease
The review of existing studies does not reveal a sus-tained association between the two diseases. Lin et al
recently did a retrospective study of POAG patients that were followed for 8 years to determine if there was an association between these two diseases. They found that POAG is not a predictor of PD.35
VI. sleeP dIsturBances
a. sleep apnea syndrome
Recent meta-analysis found that obstructive sleep apnea/hypopnea syndrome (OSAHS) patients have an increased risk of glaucoma.36,37 Pérez-Rico and co-workers also reviewed this topic suggesting that patients with severe OSAHS should have an ophthalmic evaluation, and that in glaucoma patients, especially those with NTG and disease progression despite treatment, a screening for sleep apnea syndrome should be recommended.38 However, as recom-mended by Shi et al, prospective cohort and interventional studies are needed to confirm whether OSAHS is an inde-pendent risk factor for glaucoma.39
VII. mIscellaneous
A- Empty sella: Glaucomatous excavation is observed in empty sella syndrome and possible associations between NTG and this syndrome have been des-cribed. Two mechanisms purposed were first the resulting mechanical traction and second, vascular ischemia, induced by downward pulling of the optic chiasm and by retraction of the posterior communi-cating arteries, respectively.
Until date is unclear whether there is an association between NTG and empty sella syndrome.
B- Ischemic brain lesions: A study found imagiologic signs of ischemic changes in brain MRI in 32 of 94 NTG patients.44 Supported by other studies these findings reflect a vascular cause in some glaucoma patients possibly due to cerebral small-vessel ische-mia. But until larger confirmatory studies are perfor-med a routine MRI is not recommended in glaucoma suspects.
C- Hearing Loss: Various studies suggest a relationship between POAG and neurosensorial hearing loss. After reviewing the existing studies Pache and Flammer concluded that larger epidemiological stu-dies are necessary before a true relationship can be established.
D- Helicobacter Pylori: H. pylori is thought to be associated with the development of autoimmune sequelae observed in neuropathies and with some
autoimmune conditions such as Sjogren syndrome. Kounturas et al found that H. pylori infection was histologically confirmed in 87.5% of the POAG patients, but only in 46.7% of the controls.45 Moreo-ver, 68% of glaucoma patients and 30% of anaemic control participants were seropositive for H. pylori. In a more recent prospective, non-randomized, com-parative study, the same group demonstrated higher levels of H. pylori-specific IgG antibody levels in the aqueous humour and serum of patients with POAG when compared to age-matched cataract patients. The authors hypothesized that H. pylori antibodies may circulate in the bloodstream and enter the aqueous humour via the blood-aqueous humour barrier. In the aqueous, the antibodies might reach a level sufficient to impact the development or progression of glaucoma.45
In contrast, Galloway et al could not establish an association between H. pylori infection and POAG. Seropositivity for H. pylori was found to be higher in patients with glaucoma (26.0%) than in controls (20.2%), this finding, however, did not reach statis-tical significance.46
H. pylori infection may be linked to glaucoma, nevertheless experimental and prospective multi-center epidemiologic evaluation studies are needed to validate this hypothesis.
conclusIons
POAG is a multifactorial disease that nowadays is seeing a change of spectre. Besides affecting the eye, seve-ral studies show an association with systemic findings, par-ticularly in NTG. This is important, as these patients might need a more profound evaluation with future implications in observation, follow-up and treatment. Further clinical trials, especially randomized clinical trials, are necessary to confirm newly developed medications safety and utility.
references
1. Pache M, Flammer J. A sick eye in a sick body? Syste-mic findings in patients with primary open-angle glau-coma. Surv Ophthalmol. 2006 May-Jun;51(3):179-212. 2. Graham SL, Drance SM. Nocturnal hypotension: role
in glaucoma progression. Surv Ophthalmol 43(Suppl 1): S10--S16, 1999
3. Tokunaga T, Kashiwagi K, Tsumura T, Taguchi K,
Tsukahara S. Association between nocturnal blood pressure reduction and progression of visual field defect in patients with primary open-angle glaucoma or normal-tension glaucoma. Jpn J Ophthalmol. 2004 Jul-Aug;48(4):380-5.
4. Gherghel D, Hosking SL, Cunliffe IA. Abnormal syste-mic and ocular vascular response to temperature provo-cation in primary open-angle glaucoma patients: a case for autonomic failure? Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3546-54.
5. Gherghel D, Hosking SL, Orgül S. Autonomic nervous system, circadian rhythms, and primary open-angle glau-coma. Surv Ophthalmol. 2004 Sep-Oct;49(5):491-508. 6. Kiuchi T, Motoyama Y, Oshika T. Relationship of
pro-gression of visual field damage to postural changes in intraocular pressure in patients with normal-tension glaucoma. Ophthalmology. 2006 Dec;113(12):2150-5. 7. Charlson ME et al. Nocturnal systemic hypotension
increases the risk of glaucoma progression. Ophthalmo-logy. 2014 Oct;121(10):2004-12.
8. Gasser P, Flammer J: Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high- tension glaucoma. Am J Ophthalmol 111:585--8, 1991 9. Emre M, Orgu ̈l S, Haufschild T, et al: Increased plasma
endothelin-1 levels in patients with progressive open angle glaucoma. Br J Ophthalmol 89:60--3, 2005 10. Terelak-Borys B, Czechowicz-Janicka K.
Investiga-tion into the vasospastic mechanisms in the patho-genesis of glaucomatous neuropathy. Klin Oczna. 2011;113(7-9):201-8.
11. Kunimatsu S1, Mayama C, Tomidokoro A, Araie M. Plasma endothelin-1 level in Japanese nor-mal tension glaucoma patients. Curr Eye Res. 2006 Sep;31(9):727-31.
12. Chen HY1, Chang YC, Chen WC, Lane HY. Association between plasma endothelin-1 and severity of different types of glaucoma. J Glaucoma. 2013 Feb;22(2):117-22. doi: 10.1097/IJG.0b013e31822e8c65.
13. Cursiefen C, Wisse M, Cursiefen S, Jünemann A, Martus P, Korth M. Migraine and tension headache in high-pressure and normal-pressure glaucoma. Am J Ophthalmol. 2000 Jan;129(1):102-4.
14. Patel HY1, Buys YM1, Trope GE. Nailfold capillaros-copy assessment in patients with glaucoma with a cur-rent optic disc hemorrhage. Can J Ophthalmol. 2015 Apr;50(2):155-8.
15. Park HY1, Park SH, Oh YS, Park CK. Nail bed hemor-rhage: a clinical marker of optic disc hemorrhage in patients with glaucoma. Arch Ophthalmol. 2011 Oct;129(10):1299-304
16. Riccadonna M, Covi G, Pancera P, Presciuttini B, Babi-ghian S, Perfetti S, Bonomi L, Lechi A. Autonomic system activity and 24-hour blood pressure variations in subjects with normal- and high-tension glaucoma. J Glaucoma. 2003 Apr;12(2):156-63.
17. Wax MB, Barrett DA, Pestronk A: Increased inci-dence of paraproteinemia and autoantibodies in patients with nor- mal-pressure glaucoma. Am J Ophthalmol 117:561--8, 1994
18. Romano C, Barrett DA, Li Z, et al: Anti-rhodopsin anti-bodies in sera from patients with normal-pressure glau-coma. Invest Ophthalmol Vis Sci 36:1968--75, 1995 19. Tezel G, Edward DP, Wax MB: Serum autoantibodies
to optic nerve head glycosaminoglycans in patients with glaucoma. Arch Ophthalmol 117:917--24, 1999 20. Yang J, Tezel G, Patil RV, et al: Serum autoantibody
against glutathione S-transferase in patients with glau-coma. Invest Ophthalmol Vis Sci 42:1273--6, 2001 21. Ellis JD, Morris AD, MacEwen CJ: Should diabetic
patients be screened for glaucoma? DARTS/MEMO Collaboration. Br J Ophthalmol 83:369--72, 1999 22. Ellis JD1, Evans JM, Ruta DA, Baines PS, Leese G,
MacDonald TM, Morris AD. Glaucoma incidence in an unselected cohort of diabetic patients: is diabetes mellitus a risk factor for glaucoma? DARTS/MEMO collaboration. Diabetes Audit and Research in Tayside Study. Medicines Monitoring Unit. Br J Ophthalmol. 2000 Nov;84(11):1218-24.
23. Cockerham KP, Pal C, Jani B, et al: The prevalence and implications of ocular hypertension and glaucoma in thyroid- associated orbitopathy. Ophthalmology 104:914--7, 1997
24. Ohtsuka K, Nakamura Y: Open-angle glaucoma asso-ciated with Graves disease. Am J Ophthalmol 129:613--7, 2000
25. Haefliger IO1, von Arx G, Pimentel AR. Pathophy-siology of intraocular pressure increase and glaucoma prevalence in thyroid eye disease: a mini-review. Klin Monbl Augenheilkd. 2010 Apr;227(4):292-3
26. He J, Wu Z, Yan J, Yang H, Mao Y, Ai S, Chen Z. Clinical analysis of 106 cases with elevated intraocular pressure in thyroid-associated ophthalmopathy. Yan Ke Xue Bao. 2004 Mar;20(1):10-4.
27. Howard GM, English FP: Occurence of glaucoma in acromegalies. Arch Ophthalmol 73:765--8, 1965 28. Rozsíval P,Hampl R,Obenberger J, et al: Aqueous
humour and plasma cortisol levels in glaucoma and cataract patients. Curr Eye Res 1:391--6, 1981
29. McCarty GR1, Schwartz B. Reduced plasma corti-sol binding to albumin in ocular hypertension and
primary open-angle glaucoma. Curr Eye Res. 1999 Jun;18(6):467-76
30. Schwartz B1, Rabin PA, Wysocki A, Maritn J. Decrea-sed plasma cortisol in response to intramuscular ACTH in ocular hypertensives and primary open-angle glauco-mas. J Glaucoma. 2007 May;16(3):282-6.
31. Bayer AU, Keller ON, Ferrari F, et al: Association of glaucoma with neurodegenerative diseases with apop-totic cell death: Alzheimer’s disease and Parkinson’s disease. Am J Ophthalmol 133:135--7, 2002
32. Vickers JC, Craig JE, Stankovich J, et al: The apolipo-protein epsilon4 gene is associated with elevated risk of normal tension glaucoma. Mol Vis 8:389--93, 2002 33. Tsilis AG, Tsilidis KK, Pelidou SH, Kitsos G.
Syste-mic review of the association of the association between Alzheimer’s diasease and chronia glaucoma. Clin Ophthalmol 2014:8:2095-2104.
34. Keenan TD, Goldacre R2, Goldacre MJ. Associations between primary open angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage study. Br J Ophthalmol. 2015 Apr;99(4):524-7.
35. Lin IC, Wang YH, Wang TJ, Wang IJ, Shen YD, Chi NF, Chien LN. Glaucoma, Alzheimer’s disease, and Parkinson’s disease: an 8-year population-based follow--up study. PLoS One. 2014 Oct 2;9(9):e108938 36. Wu X, Liu H. Obstructive sleep apnea/hypopnea
syn-drome increases glaucoma risk: evidence from a meta--analysis. Int J Clin Exp Med. 2015 Jan 15;8(1):297-303 37. Liu S, Lin Y, Liu X Meta-Analysis of Association of
Obstructive Sleep Apnea With Glaucoma. J Glaucoma. 2015 Nov 10
38. Pérez-Rico C, Gutiérrez-Díaz E, Mencía-Gutiérrez E, Díaz-de-Atauri MJ, Blanco R. Obstructive sleep apnea--hypopnea syndrome (OSAHS) and glaucomatous optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2014 Sep;252(9):1345-57
39. Shi Y, Liu P, Guan J, Lu Y, Su K. Association between glaucoma and obstructive sleep apnea syndrome: a meta-analysis and systematic review. PLoS One. 2015 Feb 23;10(2):e0115625
40- Chan EW, Chiang PP, Liao J, Rees G, Wong TY, Lam JS, Aung T, Maloureux, E. Glaucoma and associated visual acuity and field loss significantly affect glau-coma-specific psychosocial functioning. Ophthalmo-logy. 2015 Mar;122(3):494-501
41. Mckean-Cowdin R, Wang Y, Wu J, Azen SP, Varma R. Impacto f visual field loss on health-related quality of life in glaucoma: the Los Angeles Latino Eye Study. Ophthalmology 2008 Jun;115(6):941-948.e1
ES, Ferrucci L, Friedman DS. Fear of falling and visual field loss from glaucoma. Ophthalmology.2012 Jul;119(7):1352-8
43. van Landingham SW, Wllis JR, Vitale S, Ramulu PY. Visual field loss and accelerometer-measured physi-cal activity in the United States. Ophthalmology 2012 Dec;119(12):2486-92
44. Suzuki J, Tomidokoro A, Araie M, et al: Visual field damage in normal-tension glaucoma patients with or without ischemic changes in cerebral magnetic reso-nance imaging. Jpn J Ophthalmol 48:340--4, 2004 45. Kountouras J, Zavos C, Chatzopoulos D, et al:
Heli-cobacter pylori and glaucoma [letter]. Ophthalmology 110:2433--4; author reply 2434, 2003
46. Galloway PH, Warner SJ, Morshed MG, et al: Helico-bacter pylori infection and the risk for open-angle glau-coma. Ophthalmology 110:922--5, 2003
47. Sena DF, Lindsley K. Neuroprotection for treatment of
glaucoma in adults. Cochrane Database Syst Rev. 2013 Feb 28;2:CD006539
48. Song W, Huang P, Zhang C. Neuroprotective thera-pies for glaucoma. Drug Des Devel Ther. 2015 Mar 11;9:1469-79.
49. Frank L, Ventimiglia R, Anderson K, Lindsay RM, Rudge JS. BDNF down-regulates neurotrophin respon-siveness, TrkB protein and TrkB mRNA levels in cul-tured rat hippocampal neurons. Eur J Neurosci. 1996; 8(6):1220–1230
50. Dreyer EB, Zurakowski D, Schumer RA, Podos SM, Lipton SA. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996;114(3):299–305.
51. Koseki N, Araie M, Tomidokoro A, et al. A placebo--controlled 3-year study of a calcium blocker on visual field and ocular circulation in glaucoma with low-normal pressure. Ophthalmology. 2008;115(11):2049–2057.
